Linked Life Data

17898043

Source:http://linkedlifedata.com/resource/pubmed/id/17898043

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2007-11-28
pubmed:abstractText
von Hippel-Lindau (VHL) disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2alpha shRNA. Invasion through Matrigel and migration in wound-healing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHL-null RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1931-857X
pubmed:author
pubmed:issnType
Print
pubmed:volume
293
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
F1836-46
pubmed:dateRevised
2011-4-28
pubmed:meshHeading
pubmed-meshheading:17898043-Blotting, Western, pubmed-meshheading:17898043-Carcinoma, Renal Cell, pubmed-meshheading:17898043-Cell Line, pubmed-meshheading:17898043-Culture Media, Serum-Free, pubmed-meshheading:17898043-Cytokines, pubmed-meshheading:17898043-Humans, pubmed-meshheading:17898043-Hypoxia-Inducible Factor 1, pubmed-meshheading:17898043-Immunoprecipitation, pubmed-meshheading:17898043-Indicators and Reagents, pubmed-meshheading:17898043-Janus Kinases, pubmed-meshheading:17898043-Kidney Neoplasms, pubmed-meshheading:17898043-Neoplasm Invasiveness, pubmed-meshheading:17898043-Plasmids, pubmed-meshheading:17898043-Suppressor of Cytokine Signaling Proteins, pubmed-meshheading:17898043-Transfection, pubmed-meshheading:17898043-Von Hippel-Lindau Tumor Suppressor Protein, pubmed-meshheading:17898043-Wound Healing
pubmed:year
2007
pubmed:articleTitle
JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism.
pubmed:affiliation
Case Western Reserve Univ., School of Medicine, Dept. of Nutrition, Research Tower, RT600, 2109 Adelbert Rd., Cleveland, OH 44106, USA. lkw@case.edu
pubmed:publicationType
Journal Article